Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial

doi:10.1001/jama.2020.24505

Randomized Controlled Trial

. 2021 Feb 23;325(8):742-750.

doi: 10.1001/jama.2020.24505.

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial

Jonathan E Sevransky^{1

2}, Richard E Rothman³, David N Hager⁴, Gordon R Bernard⁵, Samuel M Brown⁶, Timothy G Buchman^{2

7}, Laurence W Busse^{1

2}, Craig M Coopersmith^{2

7}, Christine DeWilde⁸, E Wesley Ely^{5

9

10}, Lindsay M Eyzaguirre¹¹, Alpha A Fowler⁸, David F Gaieski¹², Michelle N Gong¹³, Alex Hall¹⁴, Jeremiah S Hinson³, Michael H Hooper¹⁵, Gabor D Kelen³, Akram Khan¹⁶, Mark A Levine¹⁷, Roger J Lewis^{18

19

20

21}, Chris J Lindsell²², Jessica S Marlin²³, Anna McGlothlin¹⁹, Brooks L Moore¹⁴, Katherine L Nugent¹⁴, Samuel Nwosu²², Carmen C Polito^{1

2}, Todd W Rice⁵, Erin P Ricketts³, Caroline C Rudolph¹⁴, Fred Sanfilippo²⁴, Kert Viele^{19

25}, Greg S Martin^{1

2}, David W Wright¹⁴; VICTAS Investigators

Collaborators, Affiliations

Collaborators

VICTAS Investigators:
Katherine L Nugent, Christine Spainhour, Carmen C Polito, Brooks L Moore, Lovie Negrin, Akram Khan, Bory Kea, Olivia Krol, Ebaad Haq, Vincent Pinkert, Kelly Nguyen, Samuel M Brown, Joseph Bledsoe, Ithan Peltan, Darrin Applegate, Brent Armbruster, Quinn Montgomery, Katie Brown, Austin Daw, Michelle N Gong, Michael Aboodi, Jen T Chen, Aluko Hope, Swarna Gummadi, Brenda Lopez, Jeremiah S Hinson, David N Hager, Erin P Ricketts, Casey M Clements, Ognjen Gajic, Rahul Kashyap, Derek Vanmeter, Laurence W Busse, Mary McBride, Adit Ginde, Marc Moss, Lani Finck, Michelle Howell, Jeffrey McKeehan, Carrie Higgins, Jonathan Clare, Breana McBryde, Aaron Barksdale, Dan Kalin, Derek Kruse, Katlyn Hilz, Nida Qadir, Steven Y Chang, Rebecca Beutler, Andrea Tam, Estelle S Harris, Scott T Youngquist, Elizabeth A Middleton, Ervin Davidov, Amber Plante, Justin Belsky, Jonathan Siner, Charles Wira, Carolyn Brokowski, Jay Steingrub, Howard Smithline, Sherell Thornton-Thompson, Alpha A Fowler, Stephen Miller, Kyle Narron, Michael A Puskarich, Matthew E Prekker, Audrey Hendrickson, James Quinn, Jennifer Wilson, Joseph Levitt, Rosen Mann, Anita Visweswaran, Nina Gentile, Nathaniel Marchetti, Hannah Reimer, Faheem Guirgis, Lisa Jones, Lauren Black, Morgan Henson, Nuala J Meyer, John C Greenwood, Caroline Ittner, Emanuel Rivers, Namita Jayaprakash, Jayna Gardner-Gray, Gina Hurst, Jacqueline Pflaum, Anja Kathrin Jaehne, Jasreen Gill, Aaron Cook, David R Janz, Derek Vonderhaar, Connie Romaine, R Gentry Wilkerson, Michael T McCurdy, Dana Beach, Kyra Lasko, Richard Gill, Katherine Price, Lisa Dickson, Abhijit Duggal, Sharon E Mace, R Duncan Hite, Andrei Hastings, Jason Haukoos, Ivor Douglas, Stacy Trent, Carolynn Lyle, Alicia Cupelo, Stephanie Gravitz, Terra Hiller, Judy Oakes, Frank LoVecchio, Pedro Quiroga, Shiloh Danley, Mary Mulrow, Amanda Encinas, Andrew Goodwin, Gregory Hall, Abigail Grady, Matthew Exline, Thomas Terndrup, Sonal Pannu, Emily Robart, Sarah Karow, D Clark Files, Lane Smith, Kevin Gibbs, Lori Flores, Stephen M Pastores, David J Shaz, Natalie Kostelecky, Chad Case, Elizabeth Wilkins, David F Gaieski, Michael Baram, Daniel Schwegler, Nicole Renzi, Jarrod M Mosier, Cameron Hypes, Elizabeth S Campbell, Michael H Hooper, Joshua Sill, Kate Mitchell, Kristin Hudock, Michael Lyons, Kari Gorder, Yousef Ahmad, Autumn Studer, Jacqueline Davis, Matthew Barrett, Jason Nomura, Jennifer Knox, Pauline Park, Ivan Co, Jakob McSparron, Robert Hyzy, Kelli McDonough, Sinan Hanna, Wesley H Self, Matthew W Semler, Margaret Hays, Raquel Bartz, Alexander Limkakeng, Katherine Sweeney, Rachael Woodburn, Munish Goyal, Akram Zaaqoq, Theresa Moriarty, John Oropello, Ziya Zhang

Affiliations

¹ Division of Pulmonary, Allergy, Critical Care, and Sleep, Emory University School of Medicine, Atlanta, Georgia.
² Emory Critical Care Center, Emory Healthcare, Atlanta, Georgia.
³ Department of Emergency Medicine, Johns Hopkins University, Baltimore, Maryland.
⁴ Division of Pulmonary Critical Care, Johns Hopkins University, Baltimore, Maryland.
⁵ Division of Pulmonary Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee.
⁶ Division of Pulmonary Critical Care, Intermountain Medical Center and University of Utah, Salt Lake City.
⁷ Department of Surgery, Emory University School of Medicine, Atlanta, Georgia.
⁸ Division of Pulmonary Critical Care, Virginia Commonwealth University, Richmond.
⁹ Johns Hopkins Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Baltimore, Maryland.
¹⁰ Veteran's Affairs Tennessee Valley Geriatric Research Education Clinical Center (GRECC), Nashville.
¹¹ Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, Maryland.
¹² Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
¹³ Department of Critical Care, Montefiore Medical Center, Bronx, New York.
¹⁴ Department of Emergency Medicine, Emory University, Atlanta, Georgia.
¹⁵ Division of Pulmonary Critical Care, Sentara Healthcare, Norfolk, Virginia.
¹⁶ Division of Pulmonary Critical Care, Oregon Health & Science University, Portland.
¹⁷ Molecular and Clinical Nutrition Section, National Institutes of Health, Bethesda, Maryland.
¹⁸ Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, California.
¹⁹ Berry Consultants LLC, Austin, Texas.
²⁰ Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
²¹ Lundquist Institute for Biomedical Innovation, Torrance, California.
²² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
²³ Vanderbilt Coordinating Center, Vanderbilt University Medical Center, Nashville, Tennessee.
²⁴ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
²⁵ Department of Biostatistics, University of Kentucky, Lexington.

PMID: 33620405
PMCID: PMC7903252
DOI: 10.1001/jama.2020.24505

Randomized Controlled Trial

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial

Jonathan E Sevransky et al. JAMA. 2021.

. 2021 Feb 23;325(8):742-750.

doi: 10.1001/jama.2020.24505.

Authors

Collaborators

VICTAS Investigators:
Katherine L Nugent, Christine Spainhour, Carmen C Polito, Brooks L Moore, Lovie Negrin, Akram Khan, Bory Kea, Olivia Krol, Ebaad Haq, Vincent Pinkert, Kelly Nguyen, Samuel M Brown, Joseph Bledsoe, Ithan Peltan, Darrin Applegate, Brent Armbruster, Quinn Montgomery, Katie Brown, Austin Daw, Michelle N Gong, Michael Aboodi, Jen T Chen, Aluko Hope, Swarna Gummadi, Brenda Lopez, Jeremiah S Hinson, David N Hager, Erin P Ricketts, Casey M Clements, Ognjen Gajic, Rahul Kashyap, Derek Vanmeter, Laurence W Busse, Mary McBride, Adit Ginde, Marc Moss, Lani Finck, Michelle Howell, Jeffrey McKeehan, Carrie Higgins, Jonathan Clare, Breana McBryde, Aaron Barksdale, Dan Kalin, Derek Kruse, Katlyn Hilz, Nida Qadir, Steven Y Chang, Rebecca Beutler, Andrea Tam, Estelle S Harris, Scott T Youngquist, Elizabeth A Middleton, Ervin Davidov, Amber Plante, Justin Belsky, Jonathan Siner, Charles Wira, Carolyn Brokowski, Jay Steingrub, Howard Smithline, Sherell Thornton-Thompson, Alpha A Fowler, Stephen Miller, Kyle Narron, Michael A Puskarich, Matthew E Prekker, Audrey Hendrickson, James Quinn, Jennifer Wilson, Joseph Levitt, Rosen Mann, Anita Visweswaran, Nina Gentile, Nathaniel Marchetti, Hannah Reimer, Faheem Guirgis, Lisa Jones, Lauren Black, Morgan Henson, Nuala J Meyer, John C Greenwood, Caroline Ittner, Emanuel Rivers, Namita Jayaprakash, Jayna Gardner-Gray, Gina Hurst, Jacqueline Pflaum, Anja Kathrin Jaehne, Jasreen Gill, Aaron Cook, David R Janz, Derek Vonderhaar, Connie Romaine, R Gentry Wilkerson, Michael T McCurdy, Dana Beach, Kyra Lasko, Richard Gill, Katherine Price, Lisa Dickson, Abhijit Duggal, Sharon E Mace, R Duncan Hite, Andrei Hastings, Jason Haukoos, Ivor Douglas, Stacy Trent, Carolynn Lyle, Alicia Cupelo, Stephanie Gravitz, Terra Hiller, Judy Oakes, Frank LoVecchio, Pedro Quiroga, Shiloh Danley, Mary Mulrow, Amanda Encinas, Andrew Goodwin, Gregory Hall, Abigail Grady, Matthew Exline, Thomas Terndrup, Sonal Pannu, Emily Robart, Sarah Karow, D Clark Files, Lane Smith, Kevin Gibbs, Lori Flores, Stephen M Pastores, David J Shaz, Natalie Kostelecky, Chad Case, Elizabeth Wilkins, David F Gaieski, Michael Baram, Daniel Schwegler, Nicole Renzi, Jarrod M Mosier, Cameron Hypes, Elizabeth S Campbell, Michael H Hooper, Joshua Sill, Kate Mitchell, Kristin Hudock, Michael Lyons, Kari Gorder, Yousef Ahmad, Autumn Studer, Jacqueline Davis, Matthew Barrett, Jason Nomura, Jennifer Knox, Pauline Park, Ivan Co, Jakob McSparron, Robert Hyzy, Kelli McDonough, Sinan Hanna, Wesley H Self, Matthew W Semler, Margaret Hays, Raquel Bartz, Alexander Limkakeng, Katherine Sweeney, Rachael Woodburn, Munish Goyal, Akram Zaaqoq, Theresa Moriarty, John Oropello, Ziya Zhang

Affiliations

¹ Division of Pulmonary, Allergy, Critical Care, and Sleep, Emory University School of Medicine, Atlanta, Georgia.
² Emory Critical Care Center, Emory Healthcare, Atlanta, Georgia.
³ Department of Emergency Medicine, Johns Hopkins University, Baltimore, Maryland.
⁴ Division of Pulmonary Critical Care, Johns Hopkins University, Baltimore, Maryland.
⁵ Division of Pulmonary Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee.
⁶ Division of Pulmonary Critical Care, Intermountain Medical Center and University of Utah, Salt Lake City.
⁷ Department of Surgery, Emory University School of Medicine, Atlanta, Georgia.
⁸ Division of Pulmonary Critical Care, Virginia Commonwealth University, Richmond.
⁹ Johns Hopkins Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Baltimore, Maryland.
¹⁰ Veteran's Affairs Tennessee Valley Geriatric Research Education Clinical Center (GRECC), Nashville.
¹¹ Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, Maryland.
¹² Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
¹³ Department of Critical Care, Montefiore Medical Center, Bronx, New York.
¹⁴ Department of Emergency Medicine, Emory University, Atlanta, Georgia.
¹⁵ Division of Pulmonary Critical Care, Sentara Healthcare, Norfolk, Virginia.
¹⁶ Division of Pulmonary Critical Care, Oregon Health & Science University, Portland.
¹⁷ Molecular and Clinical Nutrition Section, National Institutes of Health, Bethesda, Maryland.
¹⁸ Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, California.
¹⁹ Berry Consultants LLC, Austin, Texas.
²⁰ Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
²¹ Lundquist Institute for Biomedical Innovation, Torrance, California.
²² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
²³ Vanderbilt Coordinating Center, Vanderbilt University Medical Center, Nashville, Tennessee.
²⁴ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
²⁵ Department of Biostatistics, University of Kentucky, Lexington.

PMID: 33620405
PMCID: PMC7903252
DOI: 10.1001/jama.2020.24505

Erratum in

Addition of Nonauthor Collaborator Names of the VICTAS Trial.
[No authors listed] [No authors listed] JAMA. 2021 Sep 21;326(11):1072. doi: 10.1001/jama.2021.15080. JAMA. 2021. PMID: 34431980 Free PMC article. No abstract available.

Abstract

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis.

Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis.

Design, setting, and participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020.

Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone.

Main outcomes and measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality.

Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group.

Conclusions and relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference.

Trial registration: ClinicalTrials.gov Identifier: NCT03509350.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Sevransky reported receipt of a stipend from Critical Care Medicine for work as an associate editor and grants from the CDC Foundation. Dr Brown reported receipt of personal fees from Hamilton, Oxford University Press/Brigham Young University, and New York University and grants from Faron, Sedana, Janssen, the National Institutes of Health (NIH), and the Department of Defense. Dr Buchman reported that he is senior advisor and intergovernmental personnel assignment to BARDA DRIVe, detailed to the Solving Sepsis program, that he is editor in chief of Critical Care Medicine and Critical Care Explorations, and that he received grants and salary support as site principal investigator for the Surgical Critical Care Initiative managed by the Uniformed Services University of the Health Sciences. Dr Busse reported receipt of speakers bureau fees from La Jolla Pharmaceutical Company. Dr Ely reported receipt of grants from Bioxcel as a trial principal investigator and honoraria for continuing medical education teaching activities from Pfizer and Orion and serving as an unfunded investigator for Eli Lilly. Dr Fowler reported receipt of grants from the National Heart, Lung, and Blood Institute (NHLBI). Dr Gong reported receipt of grants from the NHLBI and the Agency for Healthcare Research and Quality (AHRQ). Dr Hall reported receipt of grants from the Centers for Disease Control and Prevention (CDC), Johnson and Johnson, the NIH, and Nico Corporation. Dr Hinson reported receipt of grants from the AHRQ and the CDC. Dr Khan reported receipt of grants from United Therapeutics, Janssen, Reata Pharma, and the NIH. Dr Lewis reported that he is the senior medical scientist at Berry Consultants LLC, a statistical consulting firm that specializes in adaptive clinical trial design. Dr Lindsell reported receipt of grants from the NIH, the CDC, and the Department of Defense; receipt of research contracts to his institution from Entegrion Inc, Endpoint Health Research, and bioMérieux; and holding stock options in Bioscape Digital; in addition, Dr Lindsell has a patent for risk stratification in pediatric septic shock issued to Cincinnati Children’s Hospital Medical Center. Dr Rice reported consulting for Cumberland Pharmaceuticals Inc, Avisa Pharma LLC, and Cytovale Inc. Dr Martin reported receipt of research advisory board fees from Beckman Coulter, Regeneron, and Grifols. No other disclosures were reported.

Figures

**Figure 1.. Participant Flow in the Vitamin C, Thiamine, and Steroids in Sepsis Trial**
^aCategories are not mutually exclusive; participants could have more than 1 reason.

**Figure 2.. Survival in the Intervention and Control Groups at 180 Days**
Cumulative deaths for the 180-day follow-up period are shown. Median time to death in the intervention group was 16 (interquartile range, 4-41) days and in the control group was 15 (interquartile range, 6-29) days. The proportionality P = .81, suggesting that the proportionality assumption was met.

See this image and copyright information in PMC

Comment in

Hydrocortisone, Vitamin C, and Thiamine for Treatment of Sepsis: Making Evidence Matter.
Walter KL, Seymour CW. Walter KL, et al. JAMA. 2021 Feb 23;325(8):730-731. doi: 10.1001/jama.2020.26029. JAMA. 2021. PMID: 33620384 No abstract available.
Funding and DSMB Membership in the VICTAS Clinical Trial.
Bauchner H, Fontanarosa PB, Golub RM. Bauchner H, et al. JAMA. 2021 Feb 23;325(8):751-752. doi: 10.1001/jama.2020.25952. JAMA. 2021. PMID: 33620386 No abstract available.
[Focus general intensive care medicine. Intensive care studies from 2020/2021].
Dietrich M, Beynon C, Fiedler MO, Bernhard M, Kümpers P, Hecker A, Jungk C, Nusshag C, Michalski D, Brenner T, Weigand MA, Reuß CJ. Dietrich M, et al. Anaesthesist. 2021 Oct;70(10):888-894. doi: 10.1007/s00101-021-00976-x. Epub 2021 Jul 29. Anaesthesist. 2021. PMID: 34324037 Free PMC article. German. No abstract available.

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Enhancing Patient Selection in Sepsis Clinical Trials Design Through an AI Enrichment Strategy: Algorithm Development and Validation.
Yang M, Zhuang J, Hu W, Li J, Wang Y, Zhang Z, Liu C, Chen H. Yang M, et al. J Med Internet Res. 2024 Sep 4;26:e54621. doi: 10.2196/54621. J Med Internet Res. 2024. PMID: 39231425 Free PMC article.
Reply to Yoshihiro and Taito: True Effect of Fludrocortisone for Septic Shock: Baseline Risk and Transitivity Concerns.
Teja B. Teja B. Am J Respir Crit Care Med. 2024 Nov 1;210(9):1162-1163. doi: 10.1164/rccm.202407-1437LE. Am J Respir Crit Care Med. 2024. PMID: 39213036 Free PMC article. No abstract available.
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Baljinnyam T, Fukuda S, Niimi Y, Prough D, Enkhbaatar P. Baljinnyam T, et al. Lab Anim Res. 2024 Aug 12;40(1):27. doi: 10.1186/s42826-024-00213-7. Lab Anim Res. 2024. PMID: 39135077 Free PMC article.
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Pregernig A, Held U, Schläpfer M, Beck-Schimmer B. Pregernig A, et al. BMC Med. 2024 Aug 13;22(1):330. doi: 10.1186/s12916-024-03552-3. BMC Med. 2024. PMID: 39134986 Free PMC article.
The Clinical Conundrum of Vasoplegia With Mechanical Circulatory Support Devices.
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References

1. Singer M, Deutschman CS, Seymour CW, et al. . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 - DOI - PMC - PubMed
1. Rhee C, Dantes R, Epstein L, et al. ; CDC Prevention Epicenter Program . Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA. 2017;318(13):1241-1249. doi:10.1001/jama.2017.13836 - DOI - PMC - PubMed
1. Torio CM, Moore BJ. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013 Agency for Healthcare Research and Quality; 2016. Healthcare Cost and Utilization Project Statistical Brief No. 204. - PubMed
1. Buchman TG, Simpson SQ, Sciarretta KL, et al. . Sepsis among Medicare beneficiaries, 1: the burdens of sepsis, 2012-2018. Crit Care Med. 2020;48(3):276-288. doi:10.1097/CCM.0000000000004224 - DOI - PMC - PubMed
1. Yende S, Austin S, Rhodes A, et al. . Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit Care Med. 2016;44(8):1461-1467. doi:10.1097/CCM.0000000000001658 - DOI - PMC - PubMed

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[1] Singer M, Deutschman CS, Seymour CW, et al. . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 - DOI - PMC - PubMed

[2] Singer M, Deutschman CS, Seymour CW, et al. . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 - DOI - PMC - PubMed

[3] Rhee C, Dantes R, Epstein L, et al. ; CDC Prevention Epicenter Program . Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA. 2017;318(13):1241-1249. doi:10.1001/jama.2017.13836 - DOI - PMC - PubMed

[4] Rhee C, Dantes R, Epstein L, et al. ; CDC Prevention Epicenter Program . Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA. 2017;318(13):1241-1249. doi:10.1001/jama.2017.13836 - DOI - PMC - PubMed

[5] Torio CM, Moore BJ. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013 Agency for Healthcare Research and Quality; 2016. Healthcare Cost and Utilization Project Statistical Brief No. 204. - PubMed

[6] Torio CM, Moore BJ. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013 Agency for Healthcare Research and Quality; 2016. Healthcare Cost and Utilization Project Statistical Brief No. 204. - PubMed

[7] Buchman TG, Simpson SQ, Sciarretta KL, et al. . Sepsis among Medicare beneficiaries, 1: the burdens of sepsis, 2012-2018. Crit Care Med. 2020;48(3):276-288. doi:10.1097/CCM.0000000000004224 - DOI - PMC - PubMed

[8] Buchman TG, Simpson SQ, Sciarretta KL, et al. . Sepsis among Medicare beneficiaries, 1: the burdens of sepsis, 2012-2018. Crit Care Med. 2020;48(3):276-288. doi:10.1097/CCM.0000000000004224 - DOI - PMC - PubMed

[9] Yende S, Austin S, Rhodes A, et al. . Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit Care Med. 2016;44(8):1461-1467. doi:10.1097/CCM.0000000000001658 - DOI - PMC - PubMed

[10] Yende S, Austin S, Rhodes A, et al. . Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit Care Med. 2016;44(8):1461-1467. doi:10.1097/CCM.0000000000001658 - DOI - PMC - PubMed

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Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial

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Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial

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